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\begin{document}

\title{Serum markers for the early diagnosis of intestinal anastomotic leak
after gyne-oncological operations}



\author[1]{oguzhan kuru}%
\author[1]{ilker cakir}%
\author[1]{utku akgör}%
\author[2]{serhat sen}%
\author[1]{goksen gorgulu}%
\author[1]{hasan emre ozdemir}%
\author[1]{Banu Isbilen  Basok}%
\author[1]{goksever akpinar}%
\author[1]{mehmet gokcu}%
\affil[1]{Affiliation not available}%
\affil[2]{Izmir Katip Celebi Universitesi}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective: To analyze the serum markers for the early diagnosis of
intestinal anastomotic leak (AL) after the gyne-oncological operations.
Methods: Between September 2017 and March 2021, patients with an
intestinal anastomosis performed during the gyne-oncological surgeries
were identified from a tertiary center in Turkey. As the local guideline
of the clinic, all these patients were followed by measuring serum
samples including procalcitonin (PCT) and C-reactive protein (CRP) on
postoperative day (POD) 1 through the day of discharge or the day of
re-operation for AL. Results: 12.5\% (5/40) of the patients suffered an
AL and 4 of them were re-operated. The mean albumin values on POD 3-4
and the mean platelet values on POD 1 were lower in the AL group
(p\textless{}0.05). Although it was not statistically significant
(p\textgreater{}0.05), median PCT values (ng/mL) on POD 8-10 were higher
in the AL group compared with no leak group. The best cutt-off point for
PCT on POD 9 was determined to be 0.11 ng/mL (AUC: 0.917, Sensitivity =
\%100.0, specifity = \%66.7, positive predictive value = \%66.7,
negative predictive value = \%100.0). Conclusion: Serum PCT and CRP
concentrations were not found to be helpfull for the early diagnosis of
AL in patients operated for gyne-oncological malignancies. Low levels of
albumin and platelets in the first days after the operation may be clue
for a possible AL.%
\end{abstract}%



\sloppy


\textbf{Abstract}

\textbf{Objective:} To analyze the serum markers for the early diagnosis
of intestinal anastomotic leak (AL) after the gyne-oncological
operations.

\textbf{Methods} : Between September 2017 and March 2021, patients with
an intestinal anastomosis performed during the gyne-oncological
surgeries were identified from a tertiary center in Turkey. As the local
guideline of the clinic, all these patients were followed by measuring
serum samples including procalcitonin (PCT) and C-reactive protein (CRP)
on postoperative day (POD) 1 through the day of discharge or the day of
re-operation for AL.

\textbf{Results} : 12.5\% (5/40) of the patients suffered an AL and 4 of
them were re-operated. The mean albumin values on POD 3-4 and the mean
platelet values on POD 1 were lower in the AL group (p\textless{}0.05).
Although it was not statistically significant (p\textgreater{}0.05),
median PCT values (ng/mL) on POD 8-10 were higher in the AL group
compared with no leak group. The best cutt-off point for PCT on POD 9
was determined to be 0.11 ng/mL (AUC: 0.917, Sensitivity = \%100.0,
specifity = \%66.7, positive predictive value = \%66.7, negative
predictive value = \%100.0).

\textbf{Conclusion:} Serum PCT and CRP concentrations were not found to
be helpfull for the early diagnosis of AL in patients operated for
gyne-oncological malignancies. Low levels of albumin and platelets in
the first days after the operation may be clue for a possible AL.

\textbf{Keywords} : Procalcitonin; Anastomotic leak; Early diagnosis.

\textbf{What's already known about this topic?}

Previous studies have shown that inflammatory biomarkers like
procalcitonin and C-reactive protein may be useful in the early
diagnosis of anastomotic leakage after major surgeries.

\textbf{What does this article add?}

Serum procalcitonin and C-reactive protein concentrations were not found
to be helpful for the early diagnosis of AL in patients operated for
gyne-oncological malignancies. Low levels of albumin and platelets in
the first days after the operation may be a clue for a possible
anastomotic leakage.

\textbf{INTRODUCTION}

Anastomotic leak (AL) after intestinal surgery has a dramatical impact
on patient's outcome regarding its high morbidity (35\%) and variable
mortality (4-22\%)\textsuperscript{1,2}.Although early diagnosis and
immediate intervention improves the prognosis, in many patients, due to
non-specific symptoms and indeterminate radiologic imaging, clinical
diagnosis of AL may delay untill 6-12 days after
surgery\textsuperscript{3}.

Previous studies have shown that inflammatory biomarkers like
procalcitonin (PCT) and C-reactive protein (CRP) may be useful in the
early diagnosis of AL after major surgeries\textsuperscript{4}. But, up
to now, no studies evaluating the role of these markers in the early
detection of AL after gyne-oncological operations have been found in the
literature.

In the present study, we aimed to analyze the serum markers for the
early diagnosis of AL after the gyne-oncological operations.

\textbf{MATERIALS AND METHODS}

\textbf{1. Study design and patient selection}

After obtaining the approval of institutional review board (Approval no:
2020/8-2)\textbf{,} a retrospective review of the patients who underwent
an intestinal anastomosis during the gyne-oncological surgeries between
September 2017 and March 2021 was performed at an ESGO (European Society
of Gynecological Oncology) accredited center in Turkey (Tepecik
Education and Research Hospital, Izmir). Patients' hospital files,
pathology and radiology reports, and laboratory results were throughly
reviewed. Exclusion criteria were defined as R2 cancer resection (gross
residual disease) and non-gynecological malignancies according to final
pathology report. Collected data included patient's age, body mass index
(BMI) (kg/m\textsuperscript{2}), ASA (American Society of
Anesthesiologists) score, type of the malignancy, operative procedure,
patient outcome, and the serum levels of biomarkers taken through the
hospitalization time.

\textbf{2. Clinical management}

Antibiotic prophylaxis with cefazolin was given 30 minutes before the
incision and repeated if the operation lasted more than 3 hours.
Combined antibiotic therapy (cefazolin plus metronidazole) continued
untill the day of discharge. On the day before and the morning of the
operation, Fleet Enema 133 mL rectally was applied. Abdominal catheter
was placed in all of the patients and the drain was taken out after the
patient tolerated oral intake. Nasogastric catheter was holded in the
first 24 hours. Oral intake was restricted in the first 72 hours and
started as liquid intake and progressed day by day with the status of
the bowel movements and the gas discharge. AL was suspected if the
patient had fever and/or abdominal tenderness and/or fecal drainage from
the drain/incision/vaginal cuff. All ALs were determined either by a
contrast-enhanced computed tomography (CT) and/or intraoperative
findings. Clavien-Dingo classification was used to define the AL as
major (need of re-operation) or minor (conservative
management)\textsuperscript{5}. In statistical analysis, major and minor
ALs were analyzed in the same group. Patients were allowed to discharge
if they had oral intake without vomiting, feces discharge, and no sign
of peritonitis.

\textbf{3. Analysis of PCT and CRP}

In the study period, according to local clinical guideline,
postoperative daily serum samples including PCT, CRP, leukocytes,
neutrophils, platelets, albumin were collected from postoperative day
(POD) 1 to the day of discharge or the day of re-operation for AL.

Venous blood samples were collected into plain blood collection tube
(BCT)s (BD Vacutainer\selectlanguage{ngerman}® SST II Advance Tube, 5 mL, 13x100 mm, USA). Serum
samples were separated from cellular fragments by centrifugation for
10\selectlanguage{english} minutes at 1.500\selectlanguage{english} g within one\selectlanguage{english} hour after blood sampling. Serum PCT
levels were measured by the sandwich immunoassay using an immunoassay
analyzer (Advia Centaur XP, Siemens Healthineers, Erlangen, Germany).
The functional assay sensitivity of the Advia Centaur BRAHMS PCT is 0.05
ng/mL with an analytical range as 0.02-75 ng/mL. The reference range for
a healthy adult population is lower than 0.1 ng/mL. A value of 2 ng/mL
represents a high risk of severe sepsis or septic shock.

CRP levels were measured by a latex-immunoturbidimetric method with an
AU5800 (Beckman Coulter Inc., USA) analyzer. The analytical range of the
test is between 0.2 to 480 mg/L. The reference range for a healthy adult
population is lower than 5 mg/L.

\textbf{4. Statistical analysis}

The study data were subjected to~~statistical analysis using the SPSS
version 20.0 (SPSS Inc, Chicago, IL). All data were expressed as
numbers, percentiles, mean, median, and standard deviation (SD). Student
t test was used for univariate analysis of the difference between
groups. Mann-Whitney U test was performed as the non-parametric test.
The receiving operating characteristic (ROC) curve and the value of area
under the curve (AUC) were used to analyze the accuracy of different
parameters to predict AL and the best cut-off point was selected.
p\textless{}0.05 was considered statistically significant.

\textbf{RESULTS}

The study population consisted of 40 patients. Mean age was 52.3 +- 12.3
years. The most common type of malignancy was ovarian cancer (70.0\%).
78.5\% of the patients were operated for primary debulking purpose.
12.5\% (5/40) of the patients suffered an AL. The clinical
characteristics of the study population were shown in Table 1.

The most common operation was rectosigmoid resection (67.5\%). The mean
operation time was 367.6 +- 122.3 minutes. A protective ostomy was opened
in 7.5\% (3/40) of the patients. Anastomosis was most frequently
performed with stapler devices (33/40, 82.5\%). In addition to
intestinal anastomosis; peritonectomy, splenectomy, appendectomy, and
lymph node (pelvic and/or paraaortic) resection were also performed in
57.5\%, 10.0\%, 50.0\%, 67.5\% of the patients, respectively (Table 2).

In both groups, PCT values \selectlanguage{english}\selectlanguage{english}tended to decrease until POD 7. Although
the PCT values \selectlanguage{english}\selectlanguage{english}started to increase from the POD 7 through POD 8-9 in
the leak group, they remained stable in the no leak group. The albumin
decrease starting from POD 1 to POD 4 was observed in the leak group
while it remained nearly stable in the no leak group through the first
10 days postoperatively. The change of mean PCT and albumin values \selectlanguage{english}\selectlanguage{english}in
anastomotic leak and no leak groups within 10 days postoperatively was
shown in Figures 1 and 2.

Postoperative 10-day PCT, albumin and platelet values \selectlanguage{english}\selectlanguage{english}were compared in
the group with and without AL. There was a statistically significant
difference between the albumin values \selectlanguage{english}\selectlanguage{english}on POD 3 (p=0.028), on POD 4
(p=0.045) and the platelet values on POD 1 (p\textless{}0.001). The mean
albumin values on POD 3-4 and the mean platelet values on POD 1 were
lower in the AL group. Although it was not statistically significant
(p\textgreater{}0.05), median PCT values (ng/mL) on POD 8, 9 and 10 were
higher in the AL group compared with no leak group (Table 3). The best
cutt-off point for PCT on POD 9 was determined to be 0.11 ng/mL (AUC:
0.917, Sensitivity = \%100.0, specifity = \%66.7, positive predictive
value = \%66.7, negative predictive value = \%100.0). Postoperative
10-day CRP, leukocyte, neutrophil, leukocyte ratio neutrophil (L/N) and
fever values \selectlanguage{english}\selectlanguage{english}were also compared in the group with and without AL, and
no statistically significant difference was found (p\textgreater{} 0.05)
(not shown in the table).

In 4 of 5 patients with AL, peritonectomy was added to the debulking
procedure. Due to severe peritonitis, 4 patients were re-operated on POD
8-10 and the leakage was classified as major. The other patient was
discharged on POD 10 before the diagnosis of AL, and re-hospitalized on
POD 15 for a rectovaginal fistula. That patient was followed
conservatively up to 2 months untill the fistula closed on its own which
provided to classify the leakage as minor. One of the patients with AL
died of multiorgan failure on POD 20. That patient was operated for
endometrial carcinosarcoma and in the removal of omental cake,
transverse colectomy and anastomosis was performed with handsewn
technique. Clinical and surgical details of the 5 patients with AL were
detailed in Table 4.

\textbf{DISCUSSION}

Our study is the first study evaluating the role of serum markers in the
early detection of AL after gyne-oncological operations. There have been
many studies showing the possible role of serum PCT and CRP in the
diagnosis of AL after elective colorectal surgeries\textsuperscript{6}.
In the study of Alvara Garcia-Granero et al., in case of major AL, PCT
and CRP were proved as reliable predictors on POD 3 to 5 with the best
value for PCT on POD 5 was 0.31 ng/ml (AUC = 0.86) (Sensitivity = 100\%,
specifity = 72\%, positive predictive value = 17\%, negative predictive
value = 100\%) \textsuperscript{7}. Also, in a recent meta-analysis, it
was concluded that PCT is a useful negative test for AL after elective
colorectal surgery with negative predictive values ranging from 95\% to
100\% (highest AUROC was 0.88 on POD 5). But, as an isolated test, poor
positive predictive values of up to 34\%, limit its use in predicting
AL\textsuperscript{8}. Different from elective colorectal surgeries, in
the surgical concept of gynecological malignancies (especially in
advanced ovarian cancer), debulking procedures including both upper and
lower abdomen and peritonectomy were needed to reach zero macroscopic
residual disease to get overall survival
advantage\textsuperscript{9,10}. So, we wanted to analyze these markers
whether they were also beneficial in the early diagnosis of AL after
gyne-oncological surgeries. And, a statistically significant difference
was found between the albumin values \selectlanguage{english}\selectlanguage{english}on POD 3 (p=0.028), on POD 4
(p=0.045) and the platelet values on POD 1 (p\textless{}0.001).
Pre-operative hypoalbuminemia is a well-known risk factor for AL, but
few studies evaluated the role of peri-operative albumin on AL after
intestinal surgeries\textsuperscript{11,12}. In the study of Shimura et
al., it was shown that lower average levels of serum albumin on POD 1
and POD 3 (HR~=~4.49, 95\% CI~=~0.77--29.58;~p\emph{~} =~0.0955) and
higher average levels of serum leukocytes on POD 1 and POD 3 (HR~=~5.62,
95\% CI~=~0.76--115.34;~\emph{p} ~=~0.0952)~were independent risk
factors for AL\textsuperscript{11}. Similarly, in our study, lower
levels of albumin on POD 3 and 4 were associated with AL. In the study
of Margarson et al., after giving intravenous hypertonic albumin
solution, serum albumin concentrations decrease significantly faster in
septic patients than in healthy controls and that was explained by
increased vascular leak of the albumin\textsuperscript{13}. But, it is
unclear whether hypoalbuminemia is the cause or result of the AL.

Interestingly, in our study, it was shown for the first time in the
literature that platelet count was associated with AL as the mean
platelet values were lower on POD 1 in the AL group. In the study of
Dewitte et al, possible mechanisms of blood platelets in sepsis
pathophysiology were reviewed\textsuperscript{14}. According to this,
beyond their roles in haemostasis, platelets are now accepted as active
actors of immune respone playing role in host defence and tissue
integrity. This interesting relation of low platelets with AL found in
our study should be further evaluated in prospective trials.

Although it was not statistically significant (p\textgreater{}0.05), in
our study, median PCT values on POD 8 to 10 were higher in the AL group.
And, PCT values increased later compared to other studies in the
literature\textsuperscript{7,15}. Intraabdominal sepsis may have delayed
in patients with AL due to our local peroperative guideline which was
different from ERAS protocol\textsuperscript{16}. Most likely reason for
this late increase of PCT in patients with AL may be antibiotic
supression during our hospitalization period. In accord to this, Charles
et al. showed that empirical antibiotic therapy was associated with a
greater decline in PCT following the onset of sepsis between day 2 and
3\textsuperscript{17}.

In contrast to previous studies, we could not find a statistically
significance between AL and postoperative CRP
levels\textsuperscript{7,18}. In a systematic review made by Singh et
al., it was shown that serum CRP level on POD 3, 4, and 5 had comparable
diagnostic accuracy for the prediction of AL with a AUROC of 0.81, 0.80,
and 0.80, respectively\textsuperscript{18}. The derived CRP cut-off
values were 172 mg/L on POD 3, 124 mg/L on POD 4 and 144 mg/L on POD 5.
And these corresponded to a negative predictive value of 97\% and a
positive predictive value of 21-23\% \textsuperscript{18}. In the study
of Smith et al., for the first time in the literature, an association of
biomarker trajectory was assessed, instead of isolated daily values. And
the trend of CRP for the first 5 days following surgery, appeared to be
highly accurate for diagnosing AL, with a daily rise of 50 units had a
sensitivity of 91\% and a negative predictive value of
99.3\%\textsuperscript{19}. Our results showed that PCT and CRP did not
work to predict AL before clinical onset of sepsis in patients operated
for gyne-oncological surgeries. After ROC analysis, the best cutt-off
point for PCT was determined to be 0.11 ng/mL on POD 9. Although this
statistical value was not useful for the early clinical management, it
could be used in patients who had vague symptoms and indeterminate
radiologic imaging. Our low number of positive cases (5 cases of AL) may
have prevented us from observing possible effect of PCT and CRP on the
early days of leakage.

Our study had some limitations. First, the study had retrospective
nature comprising consecutive patients managed on the basis of local
clinical guideline. Second, patient cohort included heteregoneus type of
malignancies and surgeries. On the other hand, PCT, previously shown to
predict AL in colorectal surgery, has been shown for the first time to
be useless in gynecological oncology. Also, different from literature,
the increase of PCT seen in AL appeared very soon that should be
supported with further studies.

In conclusion, serum PCT and CRP concentrations were not found to be
helpfull for the early diagnosis of AL in patients operated for
gyne-oncological malignancies. Low levels of albumin and platelets in
the first days after the operation may be clue for a possible AL.

\textbf{Conflict of Interest}

The authors have no conflicts of interest.

\textbf{Author contribution}

Data curation: I.C., G.G., H.E.O.

Supervision: M.G., B.I.B.

Writing -- review \& editing: O.K., U.A.

Investigation: G.A., S.S.

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\textbf{Figure Legends}

\textbf{Figure 1.} Mean procalcitonin change in anastomotic leak and no
leak groups within 10 days postoperatively.

POD=Postoperative day

\textbf{Figure 2.} Mean albumin change in anastomotic leak and no leak
groups within 10 days postoperatively.

POD=Postoperative day

\textbf{Table Legends}

\textbf{Table 1} . Clinical characteristics of the study population.

SD = Standard deviation; n = Number; \% = Column percent; CT =
Chemotherapy; CRT = Chemoradiotherapy.

\textbf{Table 2.} Surgical data of the study population.

SD = Standard deviation; n = Number; \% = Column percent

\textbf{Table 3.} Comparison of serum markers within 10 days
postoperatively in the group with and without anastomotic leakage.

POD = Postoperative day; SD =Standard deviation; p = Mann-Whitney U
test, * = Student t test

\textbf{Table 4} . Clinical and surgical details of the 5 patients with
anastomotic leakage.

POD = Postoperative day; AL = Anastomotic leakage; App= Appendectomy;
Per = Peritonectomy; Ppa = Pelvic-paraaortic lymph node resection; RS =
Rectosigmoid resection;

TC = Transverse colectomy; TJ = Total subcolectomiy plus jejunoileal
resection; S = Stapler, H = Handsewn; GS = General surgeon; GO =
Gyne-oncolog.\selectlanguage{english}
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